Insulin Aspart Injection

HIGHLIGHTS OF PRESCRIBING INFORMATION Insulin aspart is stable in infusion fluids such as 0.9% • Fluid retention and heart failure with concomitant use of thiazolidinediones (TZDs): Observe for signs and symptoms of These highlights do not include all the information sodium chloride. • Individualize and adjust the dosage of insulin aspart based heart failure; consider dosage reduction or discontinuation if needed to use insulin aspart safely and effectively. heart failure occurs (5.7). See full prescribing information for insulin aspart. on route of administration, the individual’s metabolic needs, blood glucose monitoring results and glycemic control goal • Hyperglycemia and Ketoacidosis Due to Insulin Pump Device Insulin Aspart Injection, for subcutaneous or (2.4). Malfunction: Monitor glucose and administer insulin aspart by intravenous use • Dosage adjustments may be needed with changes in physical subcutaneous injection if pump malfunction occurs (5.8). Initial U.S. Approval: 2000 activity, changes in meal patterns (i.e., macronutrient content ——— ADVERSE REACTIONS ——— ——— RECENT MAJOR CHANGES ——— or timing of food intake), changes in renal or hepatic function Adverse reactions observed with insulin aspart include: Dosage and Administration (2.1)------12/2018 or during acute illness (2.4). hypoglycemia, allergic reactions, local injection site reactions, Dosage and Administration (2.2)------11/2019 ——— DOSAGE FORMS AND STRENGTHS ——— lipodystrophy, rash, and pruritus (6). Warnings and Precautions (5.2)------11/2019 Each presentation contains 100 Units of insulin aspart per mL To report SUSPECTED ADVERSE REACTIONS, contact (U-100) Novo Nordisk Pharma, Inc. at 1-800-727-6500 or FDA ——— INDICATIONS AND USAGE ——— • 10 mL multiple-dose vial (3) at 1-800-FDA-1088 or www.fda.gov/medwatch. • Insulin aspart is rapid acting human insulin analog indicated to • 3 mL single-patient-use PenFill® cartridges for the ——— DRUG INTERACTIONS ——— improve glycemic control in adults and children with diabetes ® mellitus (1). 3 mL PenFill cartridge device (3) • Drugs that may increase the risk of hypoglycemia: antidiabetic • 3 mL single-patient-use Insulin Aspart FlexPen® (3) agents, ACE inhibitors, angiotensin II receptor blocking ——— DOSAGE AND ADMINISTRATION ——— agents, disopyramide, fibrates, fluoxetine, monoamine ——— CONTRAINDICATIONS ——— • See Full Prescribing Information for important administration oxidase inhibitors, pentoxifylline, pramlintide, propoxyphene, • During episodes of hypoglycemia (4). and dosage instructions (2.1, 2.2, 2.3, 2.4, 2.5). salicylates, somatostatin analog (e.g., octreotide), and • Hypersensitivity to insulin aspart or one of its excipients. • Subcutaneous injection (2.2): sulfonamide antibiotics (7). Inject subcutaneously within 5-10 minutes before a meal ——— WARNINGS AND PRECAUTIONS ——— • Drugs that may decrease the blood glucose lowering effect: into the abdominal area, thigh, buttocks or upper arm. • Never share an Insulin Aspart FlexPen®, PenFill® cartridge or atypical antipsychotics, corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, Rotate injection sites within the same region from one PenFill® cartridge device between patients, even if the needle phenothiazines, progestogens (e.g., in oral contraceptives), injection to the next to reduce risk of lipodystrophy and is changed (5.1). protease inhibitors, somatropin, sympathomimetic agents localized cutaneous amyloidosis. • Hyperglycemia or hypoglycemia with changes in insulin (e.g., albuterol, epinephrine, terbutaline), and thyroid Should generally be used in regimens with an regimen: Make changes to a patient’s insulin regimen (e.g., hormones (7). intermediate- or long-acting insulin. insulin strength, manufacturer, type, injection site or method • Drugs that may increase or decrease the blood glucose • Continuous Subcutaneous Infusion (Insulin Pump) (2.2): of administration) under close medical supervision with increased frequency of blood glucose monitoring (5.2). lowering effect: alcohol, beta-blockers, clonidine, lithium salts, Administer by continuous subcutaneous infusion using an and pentamidine (7). • Hypoglycemia: May be life-threatening. Increase frequency insulin pump in a region recommended in the instructions • Drugs that may blunt the signs and symptoms of from the pump manufacturer. of glucose monitoring with changes to: insulin dosage, co-administered glucose lowering medications, meal hypoglycemia: beta-blockers, clonidine, guanethidine, and Rotate the injection sites within the same region from one reserpine (7). injection to the next to reduce the risk of lipodystrophy and pattern, physical activity; and in patients with renal or hepatic localized cutaneous amyloidosis. impairments and hypoglycemia unawareness (5.3). ——— USE IN SPECIFIC POPULATIONS ——— Change the Insulin aspart in the reservoir at least every 6 • Medication Errors: Accidental mix-ups between insulin • Pediatric: Has not been studied in children with type 2 days. products can occur. Instruct patients to check insulin labels diabetes. Has not been studied in children with type 1 diabetes Change the infusion set and the infusion set insertion site before injection (5.4). <2 years of age (8.4). • Hypersensitivity reactions: Severe, life-threatening, at least every 3 days. See 17 for PATIENT COUNSELING INFORMATION and generalized allergy, including anaphylaxis, may occur. Do not mix with other insulins or diluents in the pump. FDA approved patient labeling. Discontinue insulin aspart, treat, and monitor, if indicated • Intravenous Administration (2.2): (5.5). Revised: 11/2019 Dilute insulin aspart to concentrations from 0.05 unit/ • Hypokalemia: May be life-threatening. Monitor potassium mL to 1 unit/mL insulin aspart in infusion systems using levels in patients at risk of hypokalemia and treat if indicated polypropylene infusion bags. (5.6).

FULL PRESCRIBING INFORMATION: CONTENTS* 6 ADVERSE REACTIONS 14 CLINICAL STUDIES 1 INDICATIONS AND USAGE 6.1 Clinical Trial Experience 14.1 Overview of Clinical Studies 6.2 Immunogenicity 14.2 Clinical Studies in Adult and Pediatric Patients with 2 DOSAGE AND ADMINISTRATION Type 1 Diabetes and Subcutaneous Daily Injections 2.1 Important Administration Instructions 6.3 Post Marketing Experience 7 DRUG INTERACTIONS 14.3 Clinical Studies in Adults with Type 2 Diabetes and 2.2 Route of Administration Subcutaneous Daily Injections 2.3 Dosage Information 8 USE IN SPECIFIC POPULATIONS 14.4 Clinical Studies in Adults and Pediatrics with Type 2.4 Dosage Adjustment Due to Drug Interactions 8.1 Pregnancy 1 Diabetes Using Continuous Subcutaneous Insulin 2.5 Instructions for Mixing with Other Insulins 8.2 Lactation Infusion (CSII) by External Pump 3 DOSAGE FORMS AND STRENGTHS 8.4 Pediatric Use 14.5 Clinical Studies in Adults with Type 2 Diabetes Using Continuous Subcutaneous Insulin Infusion 4 CONTRAINDICATIONS 8.5 Geriatric Use 8.6 Renal Impairment (CSII) by External Pump 5 WARNINGS AND PRECAUTIONS 8.7 Hepatic Impairment 16 HOW SUPPLIED/STORAGE AND HANDLING 5.1 Never Share an Insulin Aspart FlexPen®, PenFill® ® 10 OVERDOSAGE 16.1 How Supplied Cartridge, or PenFill Cartridge Device Between 16.2 Recommended Storage Patients 11 DESCRIPTION 17 PATIENT COUNSELING INFORMATION 5.2 Hyperglycemia or Hypoglycemia with Changes in 12 CLINICAL PHARMACOLOGY Insulin Regimen 12.1 Mechanism of Action *Sections or subsections omitted from the full prescribing 5.3 Hypoglycemia 12.2 Pharmacodynamics information are not listed. 5.4 Hypoglycemia Due to Medication Errors 12.3 Pharmacokinetics 5.5 Hypersensitivity and Allergic Reactions 5.6 Hypokalemia 13 NONCLINICAL TOXICOLOGY 5.7 Fluid Retention and Heart Failure with Concomitant 13.1 Carcinogenesis, Mutagenesis, Impairment of Use of PPAR-gamma Agonists Fertility 5.8 Hyperglycemia and Ketoacidosis Due to Insulin 13.2 Animal Toxicology and/or Pharmacology Pump Device Malfunction

1 Insulin Aspart Injection 2

FULL PRESCRIBING INFORMATION 2.5 Instructions for Mixing with Other Insulins 5.5 Hypersensitivity and Allergic Reactions 1 INDICATIONS AND USAGE Insulin aspart Insulin aspart may be mixed with NPH insulin Severe, life-threatening, generalized allergy, including anaphylaxis, can Insulin aspart is a rapid acting human insulin analog indicated to improve subcutaneous injection preparations ONLY. occur with insulin products, including insulin aspart. If hypersensitivity glycemic control in adults and children with diabetes mellitus. route • If insulin aspart is mixed with NPH reactions occur, discontinue insulin aspart; treat per standard of care and insulin, draw insulin aspart into the 2 DOSAGE AND ADMINISTRATION monitor until symptoms and signs resolve [see Adverse Reactions (6)]. syringe first and inject immediately Insulin aspart is contraindicated in patients who have had hypersensitivity 2.1 Important Administration Instructions after mixing. reactions to insulin aspart or one of the excipients [see Contraindications • Always check insulin labels before administration [see Warnings and Insulin aspart continuous Do NOT mix insulin aspart with any other Precautions (5.4)]. subcutaneous infusion insulin. (4)]. • Inspect insulin aspart visually before use. It should appear clear and route (Insulin Pump) 5.6 Hypokalemia colorless. Do not use insulin aspart if particulate matter or coloration is 3 DOSAGE FORMS AND STRENGTHS All insulin products, including insulin aspart, can cause a shift in seen. potassium from the extracellular to intracellular space, possibly leading ® Insulin aspart 100 units per mL (U-100) is available as a clear and colorless • Use Insulin Aspart FlexPen with caution in patients with visual solution for injection in: to hypokalemia. Untreated hypokalemia may cause respiratory paralysis, impairment who may rely on audible clicks to dial their dose. • 10 mL multiple-dose vial ventricular arrhythmia, and death. Monitor potassium levels in patients at ® • Use PenFill cartridges with caution in patients with visual impairment. • 3 mL single-patient-use PenFill® cartridges for the 3 mL PenFill® risk for hypokalemia if indicated (e.g., patients using potassium-lowering • Do NOT mix insulin aspart with other insulins when administering using cartridge delivery device with NovoFine® disposable needles medications, patients taking medications sensitive to serum potassium a continuous subcutaneous infusion pump. • 3 mL single-patient-use Insulin Aspart FlexPen® concentration). 2.2 Route of Administration 4 CONTRAINDICATIONS 5.7 Fluid Retention and Heart Failure with Concomitant Use Subcutaneous Injection Insulin aspart is contraindicated: of PPAR-gamma Agonists • Inject insulin aspart subcutaneously within 5-10 minutes before a meal • During episodes of hypoglycemia [see Warnings and Precautions (5.3)] Thiazolidinediones (TZDs), which are peroxisome proliferator-activated into the abdominal area, thigh, buttocks or upper arm. • In patients with hypersensitivity to insulin aspart or one of its receptor (PPAR)-gamma agonists, can cause dose-related fluid retention, • Rotate injection sites within the same region from one injection to excipients, [see Warnings and Precautions (5.5)] the next to reduce the risk of lipodystrophy and localized cutaneous particularly when used in combination with insulin. Fluid retention may amyloidosis. Do not inject into areas of lipodystrophy or localized 5 WARNINGS AND PRECAUTIONS lead to or exacerbate heart failure. Patients treated with insulin, including cutaneous amyloidosis [see Warnings and Precautions (5.2) and 5.1 Never Share an Insulin Aspart FlexPen®, PenFill® insulin aspart, and a PPAR-gamma agonist should be observed for signs Adverse Reactions (6.1, 6.3)]. Cartridge, or PenFill® Cartridge Device Between Patients and symptoms of heart failure. If heart failure develops, it should be • During changes to a patient’s insulin regimen, increase the frequency of Insulin Aspart FlexPen®, PenFill® cartridge, and PenFill® cartridge devices managed according to current standards of care, and discontinuation or blood glucose monitoring [see Warnings and Precautions (5.2)]. should never be shared between patients, even if the needle is changed. dose reduction of the PPAR-gamma agonist must be considered. • The Insulin Aspart FlexPen® dial in 1-unit increments. Patients using insulin aspart vials must never share needles or syringes 5.8 Hyperglycemia and Ketoacidosis Due to Insulin Pump with another person. Sharing poses a risk for transmission of blood-borne • Insulin aspart administered by subcutaneous injection should generally Device Malfunction be used in regimens with an intermediate- or long-acting insulin. pathogens. 5.2 Hyperglycemia or Hypoglycemia with Changes in Insulin Malfunction of the insulin pump or insulin infusion set or insulin • Insulin aspart may be diluted with Insulin Diluting Medium for degradation can rapidly lead to hyperglycemia and ketoacidosis. Prompt NovoLog® for subcutaneous injection. Diluting one part insulin aspart Regimen to nine parts diluent will yield a concentration one-tenth that of insulin Changes in an insulin regimen (e.g., insulin strength, manufacturer, type, identification and correction of the cause of hyperglycemia or ketosis is aspart (equivalent to U-10). Diluting one part insulin aspart to one injection site or method of administration) may affect glycemic control necessary. Interim subcutaneous injections with insulin aspart may be part diluent will yield a concentration one-half that of insulin aspart and predispose to hypoglycemia [see Warnings and Precautions (5.3)] or required. Patients using continuous subcutaneous insulin infusion pump (equivalent to U-50). hyperglycemia. Repeated insulin injections into areas of lipodystrophy therapy must be trained to administer insulin by injection and have alternate or localized cutaneous amyloidosis have been reported to result in Continuous Subcutaneous Infusion (Insulin Pump) insulin therapy available in case of pump failure [see How Supplied/Storage hyperglycemia; and a sudden change in the injection site (to an unaffected and Handling (16.2) and Patient Counseling Information (17)]. • Use insulin aspart in pump systems specifically indicated for insulin area) has been reported to result in hypoglycemia [see Adverse Reactions infusion. (6.1, 6.3)]. Make any changes to a patient’s insulin regimen under 6 ADVERSE REACTIONS • Train patients using continuous subcutaneous insulin fusion pump close medical supervision with increased frequency of blood glucose The following adverse reactions are also discussed elsewhere: therapy to administer insulin by injection and have alternate insulin monitoring. Advise patients who have repeatedly injected into areas of therapy available in case of pump failure. lipodystrophy or localized cutaneous amyloidosis to change the injection • Hypoglycemia [see Warnings and Precautions (5.3)] • Administer insulin aspart by continuous subcutaneous infusion in a site to unaffected areas and closely monitor for hypoglycemia. For patients • Hypersensitivity and allergic reactions [see Warnings and Precautions region recommended in the instructions from the pump manufacturer. with type 2 diabetes, dosage adjustments of concomitant anti-diabetic (5.5)] Rotate infusion sites within the same region to reduce the risk of products may be needed. • Hypokalemia [see Warnings and Precautions (5.6)] lipodystrophy or localized cutaneous amyloidosis [see Warnings and 5.3 Hypoglycemia 6.1 Clinical Trial Experience Precautions (5.2) and Adverse Reactions (6.1, 6.3)]. Hypoglycemia is the most common adverse effect of all insulin therapies, • During changes to a patient’s insulin regimen, increase the frequency of including insulin aspart. Severe hypoglycemia can cause seizures, may lead Because clinical trials are conducted under widely varying designs, the blood glucose monitoring [see Warnings and Precautions (5.2)]. to unconsciousness, may be life threatening or cause death. Hypoglycemia adverse reaction rates reported in one clinical trial may not be easily • Follow healthcare provider recommendations when setting basal and can impair concentration ability and reaction time; this may place an compared to those rates reported in another clinical trial, and may not reflect meal time infusion rate. individual and others at risk in situations where these abilities are important the rates actually observed in clinical practice. The safety of insulin aspart • Change the insulin aspart in the reservoir at least every 6 days. Follow (e.g., driving or operating other machinery). was evaluated in two treat-to-target trials of 6 months duration, conducted the insulin aspart-specific information for in-use time because insulin Hypoglycemia can happen suddenly and symptoms may differ in each in subjects with type 1 diabetes or type 2 diabetes [see Clinical Studies (14)]. aspart-specific information may differ from general pump manual individual and change over time in the same individual. Symptomatic The data in Table 1 reflect the exposure of 596 patients with type 1 diabetes instructions. awareness of hypoglycemia may be less pronounced in patients with longstanding diabetes in patients with diabetic nerve disease, in patients to insulin aspart in one clinical trial with a mean exposure duration to insulin • Change the infusion set and the infusion set insertion site at least every using medications that block the sympathetic nervous system (e.g., beta- aspart of 24 weeks. The mean age was 38.9 years. Fifty-one percent were 3 days. blockers) [see Drug Interactions (7)], or in patients who experience recurrent male, 94% were Caucasian, 2% were Black and 4% were other races. • Do NOT dilute or mix insulin aspart when administering by continuous hypoglycemia. The mean body mass index (BMI) was 25.6 kg/m2. The mean duration of subcutaneous infusion. Risk Factors for Hypoglycemia diabetes was 15.7 years and the mean HbA1c at baseline was 7.9%. • Do NOT expose insulin aspart in the pump reservoir to temperatures The data in Table 2 reflect the exposure of 91 patients with type 2 diabetes to greater than 98.6°F (37°C). The risk of hypoglycemia after an injection is related to the duration of action of the insulin and, in general, is highest when the glucose lowering effect of insulin aspart in one clinical trial with a mean exposure duration to insulin Intravenous Administration the insulin is maximal. As with all insulin preparations, the glucose lowering aspart of 24 weeks. The mean age was 56.6 years. Sixty-three percent were • Dilute insulin aspart to concentrations from 0.05 unit/mL to 1 unit/mL effect time course of insulin aspart may vary in different individuals or at male, 76% were Caucasian, 9% were Black and 15% were other races. The insulin aspart in infusion systems using polypropylene infusion bags. different times in the same individual and depends on many conditions, mean BMI was 29.7 kg/m2. The mean duration of diabetes was 12.7 years Insulin aspart is stable in infusion fluids such as 0.9% sodium chloride. including the area of injection as well as the injection site blood supply and and the mean HbA1c at baseline was 8.1%. • Administer insulin aspart intravenously ONLY under medical temperature [see Clinical Pharmacology (12.2)]. Other factors which may supervision with close monitoring of blood glucose and potassium increase the risk of hypoglycemia include changes in meal pattern (e.g., Common adverse reactions were defined as events occurring in ≥5%, levels to avoid hypoglycemia and hypokalemia [see Warnings and macronutrient content or timing of meals), changes in level of physical excluding hypoglycemia, of the population studied. Common adverse events Precautions (5.3, 5.6) and How Supplied/Storage and Handling (16.2)]. activity, or changes to co-administered medication [see Drug Interactions occurring at the same rate or greater for insulin aspart-treated subjects than (7)]. Patients with renal or hepatic impairment may be at higher risk of 2.3 Dosage Information in comparator-treated subjects during clinical trials in patients with type 1 hypoglycemia [see Use in Specific Populations (8.6, 8.7)]. diabetes mellitus and type 2 diabetes mellitus (other than hypoglycemia) are • Individualize and adjust the dosage of insulin aspart based on route Risk Mitigation Strategies for Hypoglycemia of administration, the individual’s metabolic needs, blood glucose listed in Table 1 and Table 2, respectively. monitoring results and glycemic control goal. Patients and caregivers must be educated to recognize and manage hypoglycemia. Self-monitoring of blood glucose plays an essential role in Table 1: Adverse reactions occurring in ≥ 5% of Type 1 Diabetes • Dosage adjustments may be needed with changes in physical activity, the prevention and management of hypoglycemia; increased frequency of Mellitus Adult Patients treated with insulin aspart and at the changes in meal patterns (i.e., macronutrient content or timing of blood glucose monitoring is recommended. In patients at higher risk for same rate or greater on insulin aspart than on comparator food intake), changes in renal or hepatic function or during acute hypoglycemia and patients who have reduced symptomatic awareness illness [see Warnings and Precautions (5.2, 5.3) and Use in Specific of hypoglycemia; increased frequency of blood glucose monitoring is insulin aspart + Regular Human Insulin Populations (8.6, 8.7)]. recommended. NPH (%) (n= 596) + NPH (%) (n= 286) • Dosage adjustment may be needed when switching from another insulin 5.4 Hypoglycemia Due to Medication Errors Headache 12 10 to insulin aspart [see Warnings and Precautions (5.2)]. Accidental mix-ups between insulin aspart and other insulin products have Injury accidental 11 10 2.4 Dosage Adjustment Due to Drug Interactions been reported. To avoid medication errors between insulin aspart and other Nausea 7 5 • Dosage adjustment may be needed when insulin aspart is insulins, instruct patients to always check the insulin label before each coadministered with certain drugs [see Drug Interactions (7)]. injection. Diarrhea 5 3 Insulin Aspart Injection 3

Table 2: Adverse reactions occurring in ≥ 5% of Type 2 Diabetes similar incidences. These antibodies did not cause deterioration in glycemic with major birth defects or adverse maternal or fetal outcomes. However, Mellitus Adult Patients treated with insulin aspart and at the control or necessitate increases in insulin dose. these studies cannot definitely establish the absence of any risk because of same rate or greater on insulin aspart than on comparator 6.3 Post Marketing Experience methodological limitations, including a variable duration of treatment and insulin aspart + Human Regular Insulin The following adverse reactions have been identified during post-approval small size of the majority of the trials. NPH (%) (n= 91) + NPH (%) (n= 91) use of insulin aspart. Because these adverse reactions are reported Animal Data Hyporeflexia 11 7 voluntarily from a population of uncertain size, it is generally not possible Fertility, embryo-fetal and pre-and postnatal development studies have to reliably estimate their frequency or establish a causal relationship to drug been performed with insulin aspart and regular human insulin in rats Onychomycosis 10 5 exposure. and rabbits. In a combined fertility and embryo-fetal development study Sensory disturbance 9 7 Medication errors have been reported in which other insulins have been in rats, insulin aspart was administered before mating, during mating, accidentally substituted for insulin aspart [see Warnings and Precautions and throughout pregnancy. Further, in a pre- and postnatal development Urinary tract infection 8 7 (5.4)]. study insulin aspart was given throughout pregnancy and during lactation Chest pain 5 3 Localized cutaneous amyloidosis at the injection site has occurred with to rats. In an embryo-fetal development study insulin aspart was given Headache 5 3 insulin aspart. Hyperglycemia has been reported with repeated insulin to female rabbits during organogenesis. The effects of insulin aspart did injections into areas of localized cutaneous amyloidosis; hypoglycemia has not differ from those observed with subcutaneous regular human insulin. Skin disorder 5 2 been reported with a sudden change to an unaffected injection site. Insulin aspart, like human insulin, caused pre- and post-implantation Abdominal pain 5 1 7 DRUG INTERACTIONS losses and visceral/skeletal abnormalities in rats at a dose of 200 units/ Sinusitis 5 1 kg/day (approximately 32 times the human subcutaneous dose of 1 unit/ Drugs That May Increase the Risk of Hypoglycemia kg/day, based on human exposure equivalents) and in rabbits at a dose of Severe hypoglycemia Drugs: Antidiabetic agents, ACE inhibitors, angiotensin II 10 units/kg/day (approximately three times the human subcutaneous dose Hypoglycemia is the most commonly observed adverse reaction in patients receptor blocking agents, disopyramide, fibrates, of 1 unit/kg/day, based on human exposure equivalents). No significant using insulin, including insulin aspart [see Warnings and Precautions fluoxetine, monoamine oxidase inhibitors, pentoxifylline, effects were observed in rats at a dose of 50 units/kg/day and in rabbits (5.3)]. The rates of reported hypoglycemia depend on the definition of pramlintide, propoxyphene, salicylates, somatostatin at a dose of 3 units/kg/day. These doses are approximately 8 times the hypoglycemia used, diabetes type, insulin dose, intensity of glucose analog (e.g., octreotide), and sulfonamide antibiotics. human subcutaneous dose of 1 unit/kg/day for rats and equal to the control, background therapies, and other intrinsic and extrinsic patient Intervention: Dose adjustment and increased frequency of glucose human subcutaneous dose of 1 unit/kg/day for rabbits, based on human factors. For these reasons, comparing rates of hypoglycemia in clinical trials monitoring may be required when insulin aspart is exposure equivalents. The effects are considered secondary to maternal for insulin aspart with the incidence of hypoglycemia for other products may co-administered with these drugs. hypoglycemia. be misleading and also, may not be representative of hypoglycemia rates 8.2 Lactation Drugs That May Decrease the Blood Glucose Lowering Effect of that will occur in clinical practice. Risk Summary Severe hypoglycemia was defined as hypoglycemia associated with central insulin aspart There are no data on the presence of insulin aspart in human milk, the nervous system symptoms and requiring the intervention of another person Drugs: Atypical antipsychotics (e.g., olanzapine and clozapine), or hospitalization. effects on the breastfed infant, or the effect on milk production. One small corticosteroids, danazol, diuretics, estrogens, glucagon, published study reported that exogenous insulin, including insulin aspart, The incidence of severe hypoglycemia in adult and pediatric patients isoniazid, niacin, oral contraceptives, phenothiazines, was present in human milk. However, there is insufficient information receiving subcutaneous insulin aspart with type 1 diabetes mellitus was progestogens (e.g., in oral contraceptives), protease inhibitors, to determine the effects of insulin aspart on the breastfed infant. The 17% at 24 weeks and 6% at 24 weeks, respectively [see Clinical Studies somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline), and thyroid hormones. developmental and health benefits of breastfeeding should be considered (14)]. along with the mother’s clinical need for insulin aspart, and any potential The incidence of severe hypoglycemia in adult patients receiving Intervention: Dose adjustment and increased frequency of glucose monitoring adverse effects on the breastfed infant from insulin aspart, or from the subcutaneous insulin aspart with type 2 diabetes mellitus was 10% at 24 may be required when insulin aspart is co-administered with underlying maternal condition. weeks. these drugs. The incidence of severe hypoglycemia in adult and pediatric patients 8.4 Pediatric Use Drugs That May Increase or Decrease the Blood Glucose Lowering Insulin aspart is approved for use in children for subcutaneous daily with type 1 diabetes mellitus, receiving insulin aspart via continuous Effect of insulin aspart subcutaneous insulin infusion by external pump was 2% at 16 weeks and injections and for subcutaneous continuous infusion by external insulin 10% at 16 weeks respectively. Drugs: Alcohol, beta-blockers, clonidine, and lithium salts. Pentamidine pump [see Clinical Studies (14.1, 14.2)]. Insulin aspart has not been studied No severe hypoglycemic episodes were reported in adult patients with type may cause hypoglycemia, which may sometimes be followed by in pediatric patients younger than 2 years of age. Insulin aspart has not been 2 diabetes mellitus receiving insulin aspart via continuous subcutaneous hyperglycemia. Pentamidine may cause hypoglycemia, which studied in pediatric patients with type 2 diabetes. insulin infusion by external pump at 16 weeks. may sometimes be followed by hyperglycemia. 8.5 Geriatric Use Allergic Reactions Intervention: Dose adjustment and increased frequency of glucose monitoring Of the total number of patients (n=1,375) treated with insulin aspart in may be required when insulin aspart is co-administered with 3 controlled clinical studies, 2.6% (n=36) were 65 years of age or over. Some patients taking insulin therapy, including insulin aspart have these drugs. experienced erythema, local edema, and pruritus at the site of injection. One-half of these patients had type 1 diabetes (18/1285) and the other These conditions were usually self-limiting. Severe cases of generalized Drugs That May Blunt Signs and Symptoms of Hypoglycemia half had type 2 diabetes (18/90). The HbA1c response to insulin aspart, as allergy (anaphylaxis) have been reported [see Warnings and Precautions Drugs: Beta-blockers, clonidine, guanethidine and reserpine compared to regular human insulin, did not differ by age. (5.5)]. Intervention: Increased frequency of glucose monitoring may be required 8.6 Renal Impairment Insulin initiation and glucose control intensification when insulin aspart is co-administered with these drugs. Patients with renal impairment may be at increased risk of hypoglycemia Intensification or rapid improvement in glucose control has been associated and may require more frequent insulin aspart dose adjustment and more with a transitory, reversible ophthalmologic refraction disorder, worsening 8 USE IN SPECIFIC POPULATIONS frequent blood glucose monitoring [see Warnings and Precautions (5.3) and of diabetic retinopathy, and acute painful peripheral neuropathy. However, 8.1 Pregnancy Clinical Pharmacology (12.3)]. long-term glycemic control decreases the risk of diabetic retinopathy and 8.7 Hepatic Impairment neuropathy. Risk Summary Available information from published randomized controlled trials with Patients with hepatic impairment may be at increased risk of hypoglycemia Lipodystrophy insulin aspart use during the second trimester of pregnancy have not and may require more frequent insulin aspart dose adjustment and more Administration of insulin, including insulin aspart, subcutaneously and via reported an association with insulin aspart and major birth defects or frequent blood glucose monitoring [see Warnings and Precautions (5.3) and subcutaneous insulin infusion by external pump, has resulted in lipoatrophy adverse maternal or fetal outcomes [see Data]. There are risks to the mother Clinical Pharmacology (12.3)]. (depression in the skin) or lipohypertrophy (enlargement or thickening of and fetus associated with poorly controlled diabetes in pregnancy [see 10 OVERDOSAGE tissue) in some patients [see Dosage and Administration (2.2)]. Clinical Considerations]. Excess insulin administration may cause hypoglycemia and hypokalemia Peripheral Edema In animal reproduction studies, administration of subcutaneous insulin [see Warnings and Precautions (5.3, 5.6)]. Mild episodes of hypoglycemia Insulin products, including insulin aspart, may cause sodium retention and aspart to pregnant rats and rabbits during the period of organogenesis did usually can be treated with oral glucose. Adjustments in drug dosage, meal edema, particularly if previously poor metabolic control is improved by not cause adverse developmental effects at exposures 8-times and equal to patterns, or exercise may be needed. More severe episodes with coma, intensified insulin therapy. the human subcutaneous dose of 1 unit/kg/day, respectively. Pre- and post- seizure, or neurologic impairment may be treated with intramuscular/ implantation losses and visceral/skeletal abnormalities were seen at higher Weight gain subcutaneous glucagon or concentrated intravenous glucose. Sustained exposures, which are considered secondary to maternal hypoglycemia. carbohydrate intake and observation may be necessary because Weight gain has occurred with some insulin therapies including insulin These effects were similar to those observed in rats administered regular aspart and has been attributed to the anabolic effects of insulin and the hypoglycemia may recur after apparent clinical recovery. Hypokalemia must human insulin [see Data]. be corrected appropriately. decrease in glucosuria. The estimated background risk of major birth defects is 6-10% in women 6.2 Immunogenicity with pre-gestational diabetes with a HbA1c >7% and has been reported 11 DESCRIPTION As with all therapeutic proteins, there is potential for immunogenicity. The to be as high as 20-25% in women with a HbA1c >10%. The estimated Insulin aspart (injection) is a rapid-acting human insulin analog used to detection of antibody formation is highly dependent on the sensitivity and background risk of miscarriage for the indicated population is unknown. In lower blood glucose. Insulin aspart is homologous with regular human specificity of the assay. Additionally, the observed incidence of antibody the U.S. general population, the estimated background risk of major birth insulin with the exception of a single substitution of the amino acid proline (including neutralizing antibody) positivity in an assay may be influenced defects and miscarriage in clinically recognized pregnancies is 2-4% and by aspartic acid in position B28, and is produced by recombinant DNA by several factors including assay methodology, sample handling, timing of 15-20%, respectively. technology utilizing Saccharomyces cerevisiae (baker’s yeast). Insulin sample collection, concomitant medications, and underlying disease. For Clinical Considerations aspart has the empirical formula C256H381N65079S6 and a molecular weight these reasons, comparison of the incidence of antibodies to insulin aspart in of 5825.8. the studies described below with the incidence of antibodies in other studies Disease-Associated Maternal and/or Embryo-Fetal Risk or to other products may be misleading. Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm In a 6-month study with a 6-month extension in adult subjects with type 1 delivery, and delivery complications. Poorly controlled diabetes increases diabetes, 99.8% of patients who received insulin aspart were positive for the fetal risk for major birth defects, stillbirth, and macrosomia related anti-insulin antibodies (AIA) at least once during the study, including 97.2% morbidity. that were positive at baseline. A total of 92.1% of patients who received insulin aspart were positive for anti-drug antibodies (ADA) at least once Data during the study, including 64.6% that were positive at baseline. Human Data In a phase 3 type 1 diabetes clinical trial of insulin aspart, initial increase in Published data from 5 randomized controlled trials of 441 pregnant titers of antibodies to insulin, followed by a decrease to baseline values, was women with diabetes mellitus treated with insulin aspart during the late observed in regular human insulin and insulin aspart treatment groups with 2nd trimester of pregnancy did not identify an association of insulin aspart Figure 1. Structural formula of insulin aspart. Insulin Aspart Injection 4

Insulin aspart is a sterile, aqueous, clear, and colorless solution, that 80 14 CLINICAL STUDIES contains insulin aspart 100 units/mL, glycerin 16 mg/mL, phenol 1.50 14.1 Overview of Clinical Studies mg/mL, metacresol 1.72 mg/mL, zinc 19.6 mcg/mL, disodium hydrogen phosphate dihydrate 1.25 mg/mL, sodium chloride 0.58 mg/mL and water 60 The safety and effectiveness of subcutaneous insulin aspart was compared for injection. Insulin aspart has a pH of 7.2-7.6. Hydrochloric acid 10% and/ to regular human insulin in 596 type 1 diabetes adult, 187 pediatric type 1 or sodium hydroxide 10% may be added to adjust pH. diabetes, and 91 adult type 2 diabetes patients using NPH as basal insulin 40 (see Tables 3, 4, 5). The reduction in glycated hemoglobin (HbA1c) was 12 CLINICAL PHARMACOLOGY similar to regular human insulin. 12.1 Mechanism of Action The safety and effectiveness of insulin aspart administered by continuous The primary activity of insulin, including insulin aspart is the regulation 20 subcutaneous insulin infusion (CSII) by external pump was compared ree serum insulin (mU/L) of glucose metabolism. Insulin and its analogs lower blood glucose by F to buffered regular human insulin (administered by CSII), to lispro stimulating peripheral glucose uptake, especially by skeletal muscle and (administered by CSII) and compared to insulin aspart injections and NPH 0 fat, and by inhibiting hepatic glucose production. Insulin inhibits lipolysis injection. Overall, the reduction in HbA1c was similar to the comparator. and proteolysis, and enhances protein synthesis. 0 123456 Time (h) 14.2 Clinical Studies in Adult and Pediatric Patients with Type 12.2 Pharmacodynamics 1 Diabetes and Subcutaneous Daily Injections Subcutaneous administration Figure 4. Serial mean serum free insulin concentration collected up to 6 hours following a single 0.15 units/kg Type 1 Diabetes – Adults (see Table 3) The pharmacodynamic profile of insulin aspart given subcutaneously pre-meal dose of insulin aspart (solid curve) or regular human Two 24 week, open-label, active-controlled studies were conducted to in 22 patients with type 1 diabetes is shown in Figure 2. The maximum insulin (hatched curve) injected immediately before a meal in compare the safety and efficacy of insulin aspart to regular human insulin glucose-lowering effect of insulin aspart occurred between 1 and 3 hours 22 patients with type 1 diabetes. injection in adult patients with type 1 diabetes. Because the two study after subcutaneous injection (0.15 units/kg). The duration of action for designs and results were similar, data are shown for only one study (see insulin aspart is 3 to 5 hours. The time course of action of insulin and Metabolism and Elimination Table 3). insulin analogs such as insulin aspart may vary considerably in different In a randomized, double-blind, crossover study 17 healthy Caucasian male individuals or within the same individual. The parameters of insulin aspart subjects between 18 and 40 years of age received an intravenous infusion The mean age of the trial population was 38.9 years and mean duration of activity (time of onset, peak time and duration) as designated in Figure of either insulin aspart or regular human insulin at 1.5 mU/kg/min for 120 diabetes was 15.7 years. Fifty-one percent were male. Ninety-four percent were Caucasian, 2% were Black and 4% were Other. The mean BMI was 2 should be considered only as general guidelines. The rate of insulin minutes. The mean insulin clearance was similar for the two groups with 2 absorption and onset of activity is affected by the site of injection, exercise, mean values of 1.2 L/h/kg for the insulin aspart group and 1.2 L/h/kg for the approximately 25.6 kg/m . and other variables [see Warnings and Precautions (5.3)]. regular human insulin group. Insulin aspart was administered by subcutaneous injection immediately 300 After subcutaneous administration in normal male volunteers (n=24), prior to meals and regular human insulin was administered by subcutaneous insulin aspart was eliminated with an average apparent half-life of 81 injection 30 minutes before meals. NPH insulin was administered as the 250 minutes. basal insulin in either single or divided daily doses. Changes in HbA1c were comparable for the two treatment regimens in this study (Table 3). Specific Populations 200 Pediatrics: The pharmacokinetic and pharmacodynamic properties of Table 3. Type 1 Diabetes Mellitus – Adult (insulin aspart plus NPH insulin vs. regular human insulin plus NPH insulin) 150 insulin aspart and regular human insulin were evaluated in a single dose study in 18 children (6-12 years, n=9) and adolescents (13-17 years insulin aspart + Regular Human 100 [Tanner grade ≥ 2], n=9) with type 1 diabetes. The relative differences in NPH (N=596) Insulin+ NPH (N=286) pharmacokinetics and pharmacodynamics in children and adolescents Baseline HbA1c (%)* 7.9 ± 1.1 8.0 ± 1.2 Serum glucose (mg/dL ) 50 with type 1 diabetes between insulin aspart and regular human insulin were Change from Baseline HbA1c (%) -0.1 ± 0.8 0.0 ± 0.8 similar to those in healthy adult subjects and adults with type 1 diabetes. Treatment Difference in HbA1c, Mean 0 Geriatrics: The pharmacokinetic and pharmacodynamic properties of (95% confidence interval) -0.2 (-0.3, -0.1) 0123456insulin aspart and regular human insulin were investigated in a single Time (h) dose study in 18 subjects with type 2 diabetes who were ≥ 65 years of age. *Values are Mean ± SD Figure 2. Serial mean serum glucose collected up to 6 hours The relative differences in pharmacokinetics and pharmacodynamics in Type 1 Diabetes – Pediatric (see Table 4) following a single 0.15 units/kg pre-meal dose of insulin aspart geriatric patients with type 2 diabetes between insulin aspart and regular The efficacy of insulin aspart to improve glycemic control in pediatric (solid curve) or regular human insulin (hatched curve) injected human insulin were similar to those in younger adults. patients with type 1 diabetes mellitus is based on an adequate and immediately before a meal in 22 patients with type 1 diabetes. Gender: In healthy volunteers given a single subcutaneous dose of insulin well-controlled trial of regular human insulin in pediatric patients with aspart 0.06 units/kg, no difference in insulin aspart levels was seen between Intravenous administration type 1 diabetes mellitus (Table 4). This 24-week, parallel-group study men and women based on comparison of AUC(0-10h) or Cmax. of children and adolescents with type 1 diabetes (n = 283), aged 6 to 18 A double-blind, randomized, two-way crossover study in 16 patients with Obesity: A single subcutaneous dose of 0.1 units/kg insulin aspart was years, compared two subcutaneous multiple-dose treatment regimens: type 1 diabetes demonstrated that intravenous infusion of insulin aspart administered in a study of 23 patients with type 1 diabetes and a wide range insulin aspart (n=187) or regular human insulin (n=96). NPH insulin was resulted in a blood glucose profile that was similar to that after intravenous 2 infusion with regular human insulin. Insulin aspart or human insulin was of body mass index (BMI, 22-39 kg/m ). The pharmacokinetic parameters, administered as the basal insulin. Similar effects on HbA1c were observed in AUC and Cmax, of insulin aspart were generally unaffected by BMI in the both treatment groups (Table 4). infused until the patient’s blood glucose decreased to 36 mg/dL, or until 2 2 the patient demonstrated signs of hypoglycemia (rise in heart rate and onset different groups – BMI 19-23 kg/m (N=4); BMI 23-27 kg/m (N=7); BMI Subcutaneous administration of insulin aspart and regular human insulin 27-32 kg/m2 (N=6) and BMI >32 kg/m2 (N=6). Clearance of insulin aspart have also been compared in children with type 1 diabetes (n=26) aged 2 to of sweating), defined as the time of autonomic reaction (R) (see Figure 3). 2 was reduced by 28% in patients with BMI >32 kg/m compared to patients 6 years with similar effects on HbA1c. Mean Blood Glucose (mg/dL) with BMI <23 kg/m2. 180 Renal Impairment: A single subcutaneous dose of 0.08 units/kg insulin Table 4. Pediatric Subcutaneous Administration of insulin 162 aspart was administered in a study to subjects with either normal renal aspart in Type 1 Diabetes (24 weeks; n=283) 144 function (N=6) creatinine clearance (CLcr) (> 80 ml/min) or mild (N=7; CLcr insulin aspart + Regular Human 126 = 50-80 ml/min), moderate (N=3; CLcr = 30-50 ml/min) or severe (but not NPH (N=187) Insulin+ NPH (N=96) 108 requiring hemodialysis) (N=2; CLcr = <30 ml/min) renal impairment. In this Baseline HbA1c (%)* 8.3 ± 1.2 8.3 ± 1.3 90 study, there was no apparent effect of creatinine clearance values on AUC Change from Baseline HbA1c (%) 0.1 ± 1.0 0.1 ± 1.1 72 and Cmax of insulin aspart. 54 Treatment Difference in HbA1c, Mean Hepatic Impairment: A single subcutaneous dose of 0.06 units/kg insulin (95% confidence interval) -0.2 (-0.5, 0.1) 36 aspart was administered in an open-label, single-dose study of 24 18 subjects (N=6/group) with different degree of hepatic impairment (mild, *Values are Mean ± SD 0 moderate and severe) having Child-Pugh Scores ranging from 0 (healthy 14.3 Clinical Studies in Adults with Type 2 Diabetes and 010 R–20 R–10 R R+10 R+20 R+30 R+40 R+50 R+60 volunteers) to 12 (severe hepatic impairment). In this study, there was no Subcutaneous Daily Injections Time (min) correlation between the degree of hepatic impairment and any insulin aspart Type 2 Diabetes – Adults (see Table 5) Note: The slashes on the mean profile indicate a jump on the time axis pharmacokinetic parameter. Figure 3. Mean blood glucose profiles following intravenous One six-month, open-label, active-controlled study was conducted to infusion of insulin aspart (hatched curve) and regular human 13 NONCLINICAL TOXICOLOGY compare the safety and efficacy of insulin aspart to regular human insulin in insulin (solid curve) in 16 patients with type 1 diabetes. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility patients with type 2 diabetes (Table 5). R represents the time of autonomic reaction. Standard 2-year carcinogenicity studies in animals have not been performed The mean age of the trial population was 56.6 years and mean duration 12.3 Pharmacokinetics to evaluate the carcinogenic potential of insulin aspart. In 52-week studies, of diabetes was 12.7 years. Sixty-three percent were male. Seventy-six Sprague-Dawley rats were dosed subcutaneously with insulin aspart at percent were Caucasian, 9% were Black and 15% were Other. The mean Subcutaneous administration 10, 50, and 200 units/kg/day (approximately 2, 8, and 32 times the human BMI was approximately 29.7 kg/m2. Absorption and Bioavailability subcutaneous dose of 1.0 units/kg/day, based on units/body surface area, Insulin aspart was administered by subcutaneous injection immediately In studies in healthy volunteers (total n=107) and patients with type 1 respectively). At a dose of 200 units/kg/day, insulin aspart increased prior to meals and regular human insulin was administered by subcutaneous diabetes (total n=40), the median time to maximum concentration of insulin the incidence of mammary gland tumors in females when compared to injection 30 minutes before meals. NPH insulin was administered as the aspart in these trials was 40 to 50 minutes versus 80 to 120 minutes, for untreated controls. The relevance of these findings to humans is unknown. basal insulin in either single or divided daily doses. Changes in HbA1c were regular human insulin respectively. Insulin aspart was not genotoxic in the following tests: Ames test, mouse comparable for the two treatment regimens. The relative bioavailability of insulin aspart (0.15 units/kg) compared to lymphoma cell forward gene mutation test, human peripheral blood Table 5. Subcutaneous insulin aspart Administration in Type 2 regular human insulin indicates that the two insulins are absorbed to a lymphocyte chromosome aberration test, in vivo micronucleus test in mice, Diabetes (6 months; n=176) similar extent. and in ex vivo UDS test in rat liver hepatocytes. In a clinical trial in patients with type 1 diabetes, insulin aspart and regular In fertility studies in male and female rats, at subcutaneous doses up to 200 insulin aspart + Regular Human Insulin human insulin, both administered subcutaneously at a dose of 0.15 units/kg units/kg/day (approximately 32 times the human subcutaneous dose, based NPH (N=90) + NPH (N=86) body weight, reached mean maximum concentrations of 82 and 36 mU/L, on units/body surface area), no direct adverse effects on male and female Baseline HbA1c (%)* 8.1 ± 1.2 7.8 ± 1.1 respectively. fertility, or general reproductive performance of animals was observed. Change from Baseline HbA1c (%) -0.3 ± 1.0 -0.1 ± 0.8 Distribution 13.2 Animal Toxicology and/or Pharmacology Treatment Difference in HbA1c, Mean -0.1 (-0.4, 0.1) Insulin aspart has a low binding affinity to plasma proteins (<10%), similar In standard biological assays in mice and rabbits, one unit of insulin aspart (95% confidence interval) to that seen with regular human insulin. has the same glucose-lowering effect as one unit of regular human insulin. *Values are Mean ± SD Insulin Aspart Injection 5

14.4 Clinical Studies in Adults and Pediatrics with Type 1 contamination and/or infection, or leakage of insulin, and will ensure the IFU starting with Section 1: Prepare your pen with a new needle. Make Diabetes Using Continuous Subcutaneous Insulin Infusion accurate dosing. sure the patient selects the full dose needed. (CSII) by External Pump The storage conditions are summarized in the following table: Patients Using Continuous Subcutaneous Insulin Pumps Type 1 Diabetes – Adult (see Table 6) Table 9. Storage conditions for vial, PenFill® cartridges, and • Train patients in both intensive insulin therapy with multiple injections ® and in the function of their pump and pump accessories. Two open-label, parallel design studies (6 weeks [n=29] and 16 weeks Insulin Aspart FlexPen [n=118]) compared insulin aspart to buffered regular human insulin • Instruct patients to replace insulin in the reservoir at least Insulin aspart Not in-use Not in-use In-use (opened) every 6 days; infusion sets and infusion set insertion sites (Velosulin) in adults with type 1 diabetes receiving a subcutaneous infusion presentation (unopened) (unopened) Room Temperature should be changed at least every 3 days. By following this with an external insulin pump. Room Temperature Refrigerated (below 30°C[86°F]) schedule, patients avoid insulin degradation, infusion The mean age of the trial population was 42.3 years. Thirty-nine percent (below 30°C[86°F]) set occlusion, and loss of the insulin preservative. Insulin were male. Ninety-eight percent were Caucasian and 2% were Black. 10 mL 28 days Until 28 days aspart is recommended for use in any reservoir and infusion sets The two treatment regimens had comparable changes in HbA1c. multiple-dose vial expiration date (refrigerated/room that are compatible with insulin and the specific pump. Please see temperature) recommended reservoir and infusion sets in the pump manual. Table 6. Adult Insulin Pump Study in Type 1 Diabetes (16 weeks; • Instruct patients to discard insulin exposed to temperatures higher than n=118) 3 mL 28 days Until 28 days single-patient-use expiration date (Do not refrigerate) 37°C (98.6°F). insulin aspart Buffered human PenFill® cartridges • Instruct patients to inform physician and select a new site for infusion if (N=59) insulin (N=59) infusion site becomes erythematous, pruritic, or thickened. 3 mL single-patient-use 28 days Until 28 days • Instruct patients of the risk of rapid hyperglycemia and ketosis due to Baseline HbA1c (%)* 7.3 ± 0.7 7.5 ± 0.8 Insulin Aspart expiration date (Do not refrigerate) Change from Baseline HbA (%) 0.0 ± 0.5 0.2 ± 0.6 ® pump malfunction, infusion set occlusion, leakage, disconnection or 1c FlexPen kinking, and degraded insulin. If these problems cannot be promptly Treatment Difference in HbA1c, Mean corrected, instruct patients to resume therapy with subcutaneous (95% confidence interval) 0.2 (-0.1, 0.4) Storage in External Insulin Pump: Insulin aspart in the pump reservoir should be discarded after at least every insulin injection and contact their physician [see Warnings and *Values are Mean ± SD 6 days of use or after exposure to temperatures that exceed 37°C (98.6°F). Precautions (5) and How Supplied/Storage and Handling (16.2)]. • Instruct patients of the risk of hypoglycemia from pump malfunction. Type 1 Diabetes – Pediatric (see Table 7) The infusion set and the infusion set insertion site should be changed at least every 3 days. If these problems cannot be promptly corrected, instruct patients to A randomized, 16-week, open-label, parallel design study of children and resume therapy with subcutaneous insulin injection and contact their adolescents with type 1 diabetes (n=298) aged 4-18 years compared two Storage of Diluted insulin aspart physician [see Warnings and Precautions (5) and How Supplied/Storage subcutaneous infusion regimens administered via an external insulin pump: Insulin aspart diluted with Insulin Diluting Medium for NovoLog® to and Handling (16.2)]. insulin aspart (n=198) or insulin lispro (n=100). These two treatments a concentration equivalent to U-10 or equivalent to U-50 prepared as Before using an insulin pump with insulin aspart, read the pump label to resulted in comparable changes from baseline in HbA (see Table 7). indicated under Dosage and Administration (2.2) may remain in patient use make sure the pump has been evaluated with insulin aspart. 1c at temperatures below 30°C (86°F) for 28 days. Table 7. Pediatric Insulin Pump Study in Type 1 Diabetes Storage of insulin aspart in Intravenous Infusion Fluids (16 weeks; n=298) Infusion bags prepared as indicated under Dosage and Administration (2.2) insulin aspart Lispro are stable at room temperature for 24 hours. Some insulin will be initially (N=198) (N=100) adsorbed to the material of the infusion. Baseline HbA1c (%)* 8.0 ± 0.9 8.2 ± 0.8 17 PATIENT COUNSELING INFORMATION Change from Baseline HbA1c (%) -0.1 ± 0.8 -0.1 ± 0.7 Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Treatment Difference in HbA1c, Mean -0.1 (-0.3, 0.1) (95% confidence interval) Never Share an Insulin Aspart FlexPen®, PenFill® Cartridge or ® *Values are Mean ± SD PenFill Cartridge Device Between Patients Advise patients that they must never share Insulin Aspart FlexPen®, 14.5 Clinical Studies in Adults with Type 2 Diabetes Using PenFill® cartridge or PenFill® cartridge devices with another person even Continuous Subcutaneous Insulin Infusion (CSII) by if the needle is changed, because doing so carries a risk for transmission External Pump of blood-borne pathogens. Advise patients using insulin aspart vials not Type 2 Diabetes – Adults (see Table 8) to share needles or syringes with another person. Sharing poses a risk for transmission of blood-borne pathogens [see Warnings and Precautions An open-label, 16-week parallel design trial compared pre-prandial insulin (5.1)]. aspart injection in conjunction with NPH injections to insulin aspart Hyperglycemia or Hypoglycemia administered by continuous subcutaneous infusion in 127 adults with type 2 diabetes. Inform patients that hypoglycemia is the most common adverse reaction with insulin. Instruct patients on self-management procedures including The mean age of the trial population was 55.1 years. Sixty-four percent were glucose monitoring, proper injection technique, and management of male. Eighty percent were Caucasian, 12% were Black and 8% were Other. hypoglycemia and hyperglycemia, especially at initiation of insulin The mean BMI was approximately 32.2 kg/m2. aspart therapy. Instruct patients on handling of special situations such The two treatment groups had similar reductions in HbA1c (Table 8). as intercurrent conditions (illness, stress, or emotional disturbances), an inadequate or skipped insulin dose, inadvertent administration of Table 8. Pump Therapy in Type 2 Diabetes (16 weeks; n=127) an increased insulin dose, inadequate food intake, and skipped meals. insulin aspart insulin aspart Instruct patients on the management of hypoglycemia [see Warnings and pump + NPH Precautions (5.3)]. (N=66) (N=61) Inform patients that their ability to concentrate and react may be impaired as Baseline HbA1c (%)* 8.2 ± 1.4 8.0 ± 1.1 a result of hypoglycemia. Advise patients who have frequent hypoglycemia or reduced or absent warning signs of hypoglycemia to use caution when Change from Baseline HbA1c (%) -0.6 ± 1.1 -0.5 ± 0.9 driving or operating machinery. Treatment Difference in HbA1c, Mean 0.1 (-0.3, 0.4) Advise patients that changes in insulin regimen can predispose to (95% confidence interval) hyperglycemia or hypoglycemia and that changes in insulin regimen should *Values are Mean ± SD be made under close medical supervision [see Warnings and Precautions (5.2)]. 16 HOW SUPPLIED/STORAGE AND HANDLING Hypoglycemia with Medication Errors 16.1 How Supplied Instruct patients to always check the insulin label before each injection to Insulin aspart 100 units of insulin aspart per mL (U-100) is available as a avoid mix-ups between insulin products [see Warnings and Precautions clear and colorless solution for injection in: (5.3)]. 10 mL multiple-dose vial NDC 73070-100-11 Hypersensitivity Reactions ® Advise patients that hypersensitivity reactions have occurred with insulin 3 mL single-patient-use PenFill cartridges* NDC 73070-102-15 aspart. Inform patients of the symptoms of hypersensitivity reactions [see 3 mL single-patient-use Insulin Aspart FlexPen® NDC 73070-103-15 Warnings and Precautions (5.4)]. Rx only *Insulin Aspart PenFill® cartridges are designed for use with Novo Nordisk Administration Date of Issue: 11/2019 insulin delivery devices with NovoFine® disposable needles. FlexPen® can Insulin aspart must only be used if the solution is clear and colorless with Version: 2 be used with NovoFine® or NovoTwist® disposable needles. no particles visible. Instruct patients that when injecting insulin aspart, Novo Nordisk®, NovoLog®, PenFill®, Novolin®, FlexPen®, NovoFine®, and ® The Insulin Aspart FlexPen® dials in 1-unit increments. they must press and hold down the dose button until the dose counter NovoTwist are registered trademarks of Novo Nordisk A/S. shows 0 and then keep the needle in the skin and count slowly to 6 as the Patent Information: http://novonordisk-us.com/patients/products/product- 16.2 Recommended Storage prescribed dose is not completely delivered until 6 seconds later. If the patents.html Dispense in the original sealed carton with the enclosed Instructions for needle is removed earlier, the full dose may not be delivered (a possible Manufactured by: Use. under-dose may occur by as much as 20%). Inform the patient to increase Novo Nordisk A/S Unused insulin aspart should be stored in a refrigerator between 2° and 8°C the frequency of checking their blood glucose and that possible additional DK-2880 Bagsvaerd, Denmark (36° to 46°F). Do not freeze insulin aspart and do not use insulin aspart if insulin administration may be necessary. Distributed by: it has been frozen. Do not expose insulin aspart to excessive heat or light. If 0 does not appear in the dose counter after continuously pressing the dose Novo Nordisk Pharma, Inc. button, the patient may have used a blocked needle. In this case they would Insulin aspart should not be drawn into a syringe and stored for later use. not have received any insulin – even though the dose counter has moved 1-800-727-6500 Always remove and discard the needle after each injection from the Insulin from the original dose that was set. Instruct the patient to change the needle © 2002-2020 Novo Nordisk Aspart FlexPen® and store without a needle attached. This prevents as described in Section 5 of the Instructions for Use and repeat all steps in US19IA00014 1/2020 Insulin Aspart Injection 6

Patient Information Insulin Aspart Injection Do not share your Insulin Aspart FlexPen®, PenFill® cartridge or PenFill® cartridge compatible insulin delivery device with other people, even if the needle has been changed. You may give other people a serious infection, or get a serious infection from them. What is insulin aspart? • Insulin aspart is a man-made insulin that is used to control high blood sugar in adults and children with diabetes mellitus. Who should not take insulin aspart? Do not take insulin aspart if you: • are having an episode of low blood sugar (hypoglycemia). • have an allergy to insulin aspart or any of the ingredients in insulin aspart. Before taking insulin aspart, tell your healthcare provider about all your medical conditions including, if you are: • pregnant, planning to become pregnant, or are breastfeeding. • taking new prescription or over-the-counter medicines, vitamins, or herbal supplements. Before you start taking insulin aspart, talk to your healthcare provider about low blood sugar and how to manage it. How should I take insulin aspart? • Read the Instructions for Use that come with your insulin aspart. • Take insulin aspart exactly as your healthcare provider tells you to. • Insulin aspart starts acting fast. You should eat a meal within 5 to 10 minutes after you take your dose of insulin aspart. • Know the type and strength of insulin you take. Do not change the type of insulin you take unless your healthcare provider tells you to. The amount of insulin and the best time for you to take your insulin may need to change if you take different types of insulin. • Check your blood sugar levels. Ask your healthcare provider what your blood sugars should be and when you should check your blood sugar levels. • Do not reuse or share your needles with other people. You may give other people a serious infection or get a serious infection from them. • Insulin aspart can be injected under the skin (subcutaneously) of your stomach area (abdomen), buttocks, upper legs (thighs) or upper arms, or by continuous infusion under the skin (subcutaneously) through an insulin pump into an area of your body recommended in the instructions that come with your insulin pump. • Change (rotate) your injection sites within the area you choose with each dose to reduce your risk of getting lipodystrophy (pits in skin or thickened skin) and localized cutaneous amyloidosis (skin with lumps) at the injection sites. Do not use the exact same spot for each injection. Do not inject where the skin has pits, is thickened, or has lumps. Do not inject where the skin is tender, bruised, scaly or hard, or into scars or damaged skin. What should I avoid while taking insulin aspart? While taking insulin aspart do not: • Drive or operate heavy machinery, until you know how insulin aspart affects you. • Drink alcohol or use prescription or over-the-counter medicines that contain alcohol. What are the possible side effects of insulin aspart? Insulin aspart may cause serious side effects that can lead to death, including: Low blood sugar (hypoglycemia). Signs and symptoms that may indicate low blood sugar include: • dizziness or light-headedness • blurred vision • anxiety, irritability, or mood changes • sweating • slurred speech • hunger • confusion • shakiness • headache • fast heart beat Your insulin dose may need to change because of: • change in level of physical activity or exercise • increased stress • change in diet • weight gain or loss • illness Other common side effects of insulin aspart may include: • low potassium in your blood (hypokalemia), reactions at the injection site, itching, rash, serious allergic reactions (whole body reactions), skin thickening or pits at the injection site (lipodystrophy), weight gain, and swelling of your hands and feet. Get emergency medical help if you have: • trouble breathing, shortness of breath, fast heartbeat, swelling of your face, tongue, or throat, sweating, extreme drowsiness, dizziness, confusion. These are not all the possible side effects of insulin aspart. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. General information about the safe and effective use of insulin aspart. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. You can ask your pharmacist or healthcare provider for information about insulin aspart that is written for health professionals. Do not use insulin aspart for a condition for which it was not prescribed. Do not give insulin aspart to other people, even if they have the same symptoms that you have. It may harm them. What are the ingredients in insulin aspart? Active Ingredient: insulin aspart Inactive Ingredients: glycerin, phenol, metacresol, zinc, disodium hydrogen phosphate dihydrate, sodium chloride and water for injection Manufactured by: Novo Nordisk A/S; DK-2880 Bagsvaerd, Denmark For more information, call 1-800-727-6500.

This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 11/2019

© 2020 Novo Nordisk US19IA00014 1/2020 Insulin Aspart Injection 7

Instructions for Use • NPH insulin is the only type of insulin that can be mixed Insulin Aspart Injection Step 6: Turn the insulin aspart with insulin aspart. Do not mix insulin aspart with any other vial and syringe upside down type of insulin. 10 mL multiple-dose vial (100 Units/mL, U-100) and slowly pull the plunger • Insulin aspart should only be mixed with NPH insulin down until the black tip is a few if it is going to be injected right away under your skin Read this Instructions for Use before you start taking insulin aspart units past the line for your dose (subcutaneously). and each time you get a refill. There may be new information. This (See Figure F). information does not take the place of talking to your healthcare • Insulin aspart should be drawn up into the syringe before you provider about your medical condition or your treatment. draw up your NPH insulin. • Talk to your healthcare provider if you are not sure about the Supplies you will need to give your insulin aspart right way to mix insulin aspart and NPH insulin. injection: (Figure F) • 10 mL insulin aspart vial Step 10: Choose your injection • insulin syringe and needle Vial Tamper resistant cap • If there are air bubbles, tap the site and wipe the skin with an • alcohol swabs syringe gently a few times to alcohol swab. Let the injection Preparing your insulin Rubber let any air bubbles rise to the site dry before you inject your Stopper top (See Figure G). dose (See Figure J). aspart dose: (under cap) • Wash your hands with soap and water. • Before you start to prepare your injection, check the insulin aspart label to make (Figure J) sure that you are taking the right type of insulin. This (Figure G) Step 11: Insert the needle into is especially important if your skin. Push down on the you use more than 1 type of Step 7: Slowly push the plunger to inject your dose (See insulin. plunger up until the black tip Figure K). The needle should • Insulin aspart should look reaches the line for your insulin remain in the skin for at clear and colorless. Do not aspart dose (See Figure H). least 6 seconds to make use insulin aspart if it is thick, sure you have injected all cloudy, or is colored. the insulin. • Do not use insulin aspart past the expiration date printed on the label. (Figure K)

Step 1: Pull off the tamper Step 12: Pull the needle out of resistant cap (See Figure A). (Figure H) your skin. After that, you may Step 2: Wipe the rubber see a drop of insulin aspart at stopper with an alcohol swab Step 8: Check the syringe to make sure you have the right dose the needle tip. This is normal (See Figure B). of insulin aspart. and does not affect the dose you just received (See Figure L). • If you see blood after you take Step 9: Pull the syringe out of the needle out of your skin, the vial’s rubber stopper (See press the injection site lightly Figure I). with a piece of gauze or an (Figure A Figure B) alcohol swab. Do not rub the (Figure L) area. Step 3: Hold the syringe with After your injection: the needle pointing up. Pull • Do not recap the needle. Recapping the needle can lead to a down on the plunger until the needle stick injury. black tip reaches the line for • Put the empty insulin vials, used needles and syringes in a the number of units for your (Figure I) prescribed dose (See Figure C). FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles and syringes and Giving your Injection: needles in your household trash. • If you do not have a FDA-cleared sharps disposal container, you • Inject your insulin aspart exactly as your healthcare provider has may use a household container that is: shown you. Your healthcare provider should tell you if you need to pinch the skin before injecting. made of a heavy-duty plastic, (Figure C) can be closed with a tight-fitting, puncture-resistant lid, • Insulin aspart can be injected under the skin (subcutaneously) of without sharps being able to come out, Step 4: Push the needle your stomach area, buttocks, upper legs or upper arms, infused upright and stable during use, through the rubber stopper in an insulin pump (continuous subcutaneous infusion into an area of your body recommended in the instructions that come leak-resistant, and properly labeled to warn of hazardous of the insulin aspart vial (See waste inside the container. Figure D). with your insulin pump), or given through a needle in your arm (intravenously) by your healthcare provider. • When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to • If you inject insulin aspart, change (rotate) your injection dispose of your sharps disposal container. There may be state or sites within the area you choose for each dose to reduce your local laws about how you should throw away used needles and risk of getting lipodystrophy (pits in skin or thickened skin) syringes. For more information about the safe sharps disposal, and localized cutaneous amyloidosis (skin with lumps) at the and for specific information about sharps disposal in the state injection sites. Do not use the same injection site for each that you live in, go to the FDA’s website at: http://www.fda.gov/ (Figure D) injection. Do not inject where the skin has pits, is thickened, or safesharpsdisposal. has lumps. Do not inject where the skin is tender, bruised, scaly Do not dispose of your used sharps disposal container in your or hard, or into scars or damaged skin. Step 5: Push the plunger all household trash unless your community guidelines permit this. the way in. This puts air into • If you use insulin aspart in an insulin pump, you should change Do not recycle your used sharps disposal container. your insertion site every 3 days. Insulin aspart should be given the insulin aspart vial (See How should I store insulin aspart? Figure E). into an area of your body recommended in the instructions that come with your insulin pump. Change (rotate) your insertion • Do not freeze insulin aspart. Do not use insulin aspart if it has sites within the area you choose for each insertion to reduce been frozen. your risk of getting lipodystrophy (pits in skin or thickened skin) • Keep insulin aspart away from heat or light. and localized cutaneous amyloidosis (skin with lumps) at the • All unopened vials: insertion sites. Do not insert into the exact same spot for each Store unopened insulin aspart vials in the refrigerator at insertion. Do not insert where the skin has pits, is thickened, 36°F to 46°F (2°C to 8°C). or has lumps. Do not insert where the skin is tender, bruised, Unopened vials may be used until the expiration date printed (Figure E) scaly or hard, or into scars or damaged skin. The insulin in the on the label, if they have been stored in the refrigerator. reservoir should be changed at least every 6 days even if you Unopened vials should be thrown away after 28 days, if they have not used all of the insulin. are stored at room temperature. • If you use insulin aspart in an insulin pump, see your insulin pump manual for instructions or talk to your healthcare provider. Insulin Aspart Injection 8

• After vials have been opened: Opened insulin aspart vials can be stored in the refrigerator at 36°F to 46°F (2°C to 8°C) or at room temperature below 86°F (30°C). Throw away all opened insulin aspart vials after 28 days, even if they still have insulin left in them. General information about the safe and effective use of insulin aspart • Always use a new syringe and needle for each injection. • Do not share syringes or needles. • Keep insulin aspart vials, syringes, and needles out of the reach of children.

This Instructions for Use has been approved by the U.S. Food and Drug Administration. Manufactured by: Novo Nordisk A/S DK-2880 Bagsvaerd, Denmark Distributed by: Novo Nordisk Pharma, Inc. 1-800-727-6500 Revised: 11/2019 © 2002-2020 Novo Nordisk US19IA00014 1/2020 Insulin Aspart FlexPen® 9

Instructions For Use C. Pull off the big NovoFine® Do not use the cartridge scale printed on the cartridge to ® ® Insulin Aspart FlexPen® outer needle cap NovoFine Plus NovoTwist measure your dose of insulin. (see diagram C). Injection C Giving the injection Introduction Do the injection exactly as shown to you by your healthcare Please read the following instructions carefully before using your provider. Your healthcare provider should tell you if you need to Insulin Aspart FlexPen®. pinch the skin before injecting. Wipe the skin with an alcohol swab Do not share your Insulin Aspart FlexPen® with other and let the area dry. people, even if the needle has been changed. You may Insulin aspart can be injected under the skin (subcutaneously) of your stomach area, buttocks, upper legs (thighs), or upper arms. give other people a serious infection, or get a serious ® infection from them. D. Pull off the inner NovoFine Change (rotate) your injection sites within the area you choose for needle cap and throw NovoFine® Plus NovoTwist® Insulin Aspart FlexPen® is a disposable, single-patient use, each dose to reduce your risk of getting lipodystrophy (pits in skin it away (dispose of it) D or thickened skin) and localized cutaneous amyloidosis (skin with dial-a-dose insulin pen. You can select doses from 1 to 60 units (see diagram D). in increments of 1 unit. Insulin Aspart FlexPen® is designed to be lumps) at the injection sites. Do not use the same injection site for used with NovoFine®, NovoFine® Plus or NovoTwist® needles. each injection. Do not inject where the skin has pits, is thickened, or has lumps. Do not inject where the skin is tender, bruised, scaly People who are blind or have vision problems should not use this or hard, or into scars or damaged skin. Pen without help from a person trained to use the Pen. I. Insert the needle into your skin. I Getting ready Inject the dose by pressing the Make sure you have the following items: Always use a new needle for each injection to make sure the push-button all the way in until • Insulin Aspart FlexPen® needle is free of germs (sterile) and to prevent blocked needles. the 0 lines up with the pointer (see • New NovoFine®, NovoFine® Plus or NovoTwist® needle Do not reuse or share your needles with other people. You may diagram I). Be careful only to push give other people a serious infection, or get a serious infection the button when injecting. 0 • Alcohol swabs 4 from them. Turning the dose selector will not 6 ® Insulin Aspart FlexPen Be careful not to bend or damage the needle before use. inject insulin. Pen cap To reduce the risk of unexpected needle sticks, never put the J. Keep the needle in the skin for inner needle cap back on the needle. at least 6 seconds, and keep the J push-button pressed all the way in Giving the airshot before each injection until the needle has been pulled out Before each injection small amounts of air may collect in the Rubber Cartridge Pointer Push- from the skin (see diagram J). This cartridge during normal use. To avoid injecting air and to ensure will make sure that the full dose has stopper Cartridge scale Dose button proper dosing: selector been given. E. Turn the dose selector to select 2 You may see a drop of insulin at the needle tip. This is E units (see diagram E). normal and has no effect on the dose you just received. If blood appears after you take the needle out of your skin, press the injection site lightly with an alcohol swab. Do not NovoFine® rub the area. Big outer Inner needle Protective After the injection needle cap cap Needle tab 2 units Do not recap the needle. Recapping can lead to a needle stick selected injury. Remove the needle from the Insulin Aspart FlexPen® after each injection and dispose of it. This helps to prevent infection, F. Hold your Insulin Aspart FlexPen® leakage of insulin, and will help to make sure you inject the right F NovoFine® Plus with the needle pointing up. dose of insulin. Tap the cartridge gently with your Big outer Inner needle Protective If you do not have a sharps container, carefully slip the needle into needle cap cap Needle tab finger a few times to make any air the outer needle cap. Safely remove the needle and throw it away as bubbles collect at the top of the soon as you can. cartridge (see diagram F). • Put your used needles in a FDA-cleared sharps disposal G. Keep the needle pointing upwards, container right away after use. Do not throw away (dispose of) press the push-button all the way in G loose needles in your household trash. ® NovoTwist (see diagram G). The dose selector • If you do not have a FDA-cleared sharps disposal container, you Big outer Inner needle Protective returns to 0. may use a household container that is: needle cap cap Needle tab A drop of insulin should appear at made of a heavy-duty plastic, the needle tip. If not, change the can be closed with a tight-fitting, puncture-resistant lid, needle and repeat the procedure without sharps being able to come out, no more than 6 times. upright and stable during use, Preparing your Insulin Aspart FlexPen® If you do not see a drop of insulin leak-resistant, and after 6 times, do not use the Insulin Wash your hands with soap and water. Before you start to prepare ® properly labeled to warn of hazardous waste inside the your injection, check the label to make sure that you are taking Aspart FlexPen and contact Novo container. Nordisk at 1-800-727-6500. the right type of insulin. This is especially important if you take • When your sharps disposal container is almost full, you will more than 1 type of insulin. Insulin aspart should look clear and A small air bubble may remain at the needle tip, but it will not need to follow your community guidelines for the right way to colorless. Do not use your Insulin Aspart FlexPen® if the liquid be injected. dispose of your sharps disposal container. There may be state contains particles or is colored. or local laws about how you should throw away used needles Selecting your dose and syringes. For more information about the safe sharps A. Pull off the pen cap (see diagram A). A Check and make sure that the dose selector is set at 0. disposal, and for specific information about sharps disposal in Wipe the rubber stopper with an H. Turn the dose selector to the the state that you live in, go to the FDA’s website at: alcohol swab. H http://www.fda.gov/safesharpsdisposal. number of units you need to inject. The pointer should line up with Do not dispose of your used sharps disposal container in your your dose. household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container. B. Attaching the needle NovoFine® The dose can be corrected either up ® ® • When there is not enough medicine left in your Insulin Aspart Remove the protective tab NovoFine Plus NovoTwist or down by turning the dose selector FlexPen® for your prescribed dose, the Insulin Aspart FlexPen® from a disposable needle. B in either direction until the correct may be thrown away in your household trash after you have dose lines up with the pointer 5 units 4 Screw the needle tightly selected 6 removed the needle. onto your FlexPen®. (see diagram H). When turning the The Insulin Aspart FlexPen® prevents the cartridge from being It is important that the dose selector, be careful not to press completely emptied. It is designed to deliver 300 units. 24 units 24 needle is put on straight the push-button as insulin will selected come out. K. Put the pen cap on the Insulin Aspart (see diagram B). FlexPen® and store the Insulin Aspart K Never place a disposable You cannot select a dose larger than the number of units left FlexPen® without the needle attached needle on your Insulin in the cartridge. (see diagram K). Storing without Aspart FlexPen® until You will hear a click for every single unit dialed. Do not set the needle attached helps prevent you are ready to take your the dose by counting the number of clicks you hear because leaking, blocking of the needle, and injection. you may get an incorrect dose. air from entering the Pen. Insulin Aspart FlexPen® 10

How should I store Insulin Aspart FlexPen®? • Do not freeze insulin aspart. Do not use insulin aspart if it has been frozen. • Keep insulin aspart away from heat or light. • Store the Insulin Aspart FlexPen® without the needle attached. • Until first use: Store unused Insulin Aspart FlexPen® in the refrigerator at 36°F to 46°F (2°C to 8°C). Unused FlexPen® may be used until the expiration date printed on the label, if kept in the refrigerator. Unused Insulin Aspart FlexPen® stored at room temperature should be thrown away after 28 days. • In-use: Store the FlexPen® you are currently using out of the refrigerator at room temperature below 86°F (30°C) for up to 28 days. The Insulin Aspart FlexPen® you are using should be thrown away after 28 days, even if it still has insulin left in it. Maintenance For the safe and proper use of your FlexPen® be sure to handle it with care. Avoid dropping your FlexPen® as it may damage it. If you are concerned that your FlexPen® is damaged, use a new one. You can clean the outside of your FlexPen® by wiping it with a damp cloth. Do not soak or wash your FlexPen® as it may damage it. Do not refill your FlexPen®. Remove the needle from the Insulin Aspart FlexPen® after each injection. This helps to ensure sterility, prevent leakage of insulin, and will help to make sure you inject the right dose of insulin for future injections. Be careful when handling used needles to avoid needle sticks and transfer of infectious diseases. Keep your Insulin Aspart FlexPen® and needles out of the reach of children. Use Insulin Aspart FlexPen® as directed to treat your diabetes. Do not share your Insulin Aspart FlexPen® or needles with other people. You may give other people a serious infection, or get a serious infection from them. Always use a new needle for each injection. Novo Nordisk is not responsible for harm due to using this insulin pen with products not recommended by Novo Nordisk. As a precautionary measure, always carry a spare insulin delivery device in case your Insulin Aspart FlexPen® is lost or damaged. Remember to keep the disposable Insulin Aspart FlexPen® with you. Do not leave it in a car or other location where it can get too hot or too cold.

This Instructions for Use has been approved by the U.S. Food and Drug Administration. Revised: 11/2019 Insulin Aspart PenFill® 11

Instructions for Use How to use the Insulin Aspart PenFill® cartridge Check the insulin flow Insulin Aspart PenFill® 3 mL cartridge • Wash your hands with soap and water. Step 5: 100 Units/mL (U-100) • Before you start to prepare your injection, check the Insulin • Small amounts of air may collect in the cartridge during normal Injection Aspart PenFill® cartridge label to make sure that it contains use. You must do an airshot before each injection to avoid • Do not share your PenFill® cartridge or PenFill® the insulin you need. This is especially important if you take injecting air and to make sure you receive the prescribed dose of cartridge compatible insulin delivery device with other more than 1 type of insulin. your medicine. people, even if the needle has been changed. You may • The tamper-resistant foil should be in place before the first use. • Do the airshot as described in the instruction manual that comes give other people a serious infection, or get a serious If the foil has been broken or removed before your first use of the with your device. cartridge, do not use it. Call Novo Nordisk at 1-800-727-6500. • Keep testing your Novo infection from them. ® • Your healthcare provider should show you or your caregiver how • Carefully look at the cartridge and the insulin inside it. Nordisk 3 mL PenFill to inject insulin aspart the right way before you inject it for the Check that the insulin aspart cartridge: cartridge compatible first time. is not damaged, for example cracked or leaking insulin delivery device ® is not loose on the threaded end until you see insulin at the • Insulin Aspart PenFill cartridge 100 Units/mL is a needle tip. If you still do prefilled, single-patient-use cartridge containing 300 • Insulin aspart should not see a drop of insulin units of insulin aspart. look clear and colorless. Threaded end ® after 6 times, change the • After you insert the PenFill cartridge in your device, you can Do not use insulin needle and repeat this use it for multiple injections. Read the instruction manual aspart if it is cloudy or step. This makes sure that comes with your insulin delivery device for complete colored or if the threaded ® that any air bubbles are instructions on how to use the PenFill cartridge with the device. end is loose (See Figure removed and that insulin • People who are blind or have vision problems should not use B). is getting through the (Figure G) this PenFill® cartridge without help from a person trained to use needle (See Figure G). ® the PenFill cartridge with the device. Step 1: (Figure B) ® Select your dose • If using a new Insulin Aspart PenFill cartridge, start with • Insert a 3 mL cartridge Step 1. Step 6: ® with the threaded end • If the Insulin Aspart PenFill cartridge has already been used, first into your Novo • Check to make sure that the dose counter is set to 0. start with Step 2. Nordisk 3 mL PenFill® • Turn the dose selector Supplies you will need to give your insulin aspart injec- cartridge compatible clockwise to select Dose Dose tion: insulin delivery device the dose you need counter selector • Insulin Aspart PenFill® cartridge (See Figure C). to inject (See Figure H). • Novo Nordisk 3 mL PenFill® cartridge compatible insulin • If you drop your device, The pointer should line up with your dose. When delivery device check the insulin cartridge 0 • 1 new NovoFine®, NovoFine® Plus, or NovoTwist® needle for damage such as turning the dose selector, 1 be careful not to press the • Alcohol swabs cracks or leaking. If your cartridge is damaged, dose button as insulin will Dose pointer • Adhesive bandage come out. You will hear throw it away and use a (Figure C) • Cotton gauze new one. a click for every single • A sharps container for throwing away used PenFill® cartridges unit dialed. Do not set Example and needles. See “After your injection” at the end of Prepare your device with a new needle the dose by counting the 12 12 units these instructions. Step 2: number of clicks you hear 13 selected because you may get an NovoFine® • Take a new needle, and tear off the paper tab. Always use a new needle for each injection to make sure the needle is free of incorrect dose. (Figure H) Outer Inner Paper germs (sterile) and to prevent blocked needles. Do not attach • Refer to your insulin delivery device manual if necessary. needle cap needle cap Needle tab a new needle to your device until you are ready to give your Inject your dose injection. Do not reuse or share your needles with other Step 7: people. You may give others a serious infection, or get Places to inject a serious infection from them. • Do the injection • Be careful not to bend ® exactly as shown to NovoFine® Plus NovoFine or damage the needle NovoFine® Plus NovoTwist® you by your healthcare Outer Inner Paper before you use it. provider. Your Upper arms needle cap needle cap Needle tab • Push the needle healthcare provider straight onto the should tell you if you Abdomen device. Turn the need to pinch the skin needle clockwise until before injecting. • Insulin aspart can be Upper thighs NovoTwist® it is on tight (See Figure D). injected under the Outer Inner Paper skin (subcutaneously) needle cap needle cap Needle tab (Figure D) of your stomach area (abdomen), buttocks, Buttocks Step 3: NovoFine® ® ® upper legs (thighs), • Pull off the outer NovoFine Plus NovoTwist or upper arms needle cap (See (See Figure I). (Figure I) PenFill® cartridge compatible insulin delivery device Figure E). Do not throw it away. You • Change (rotate) your injection sites within the area will need it after the you choose for each dose to reduce your risk of getting injection to safely lipodystrophy (pits in skin or thickened skin) and remove the needle. localized cutaneous amyloidosis (skin with lumps) at Pen cap the injection sites. Do not use the same injection site Dose pointer for each injection. Do not inject where the skin has (Figure E) pits, is thickened, or has lumps. Do not inject where the skin is tender, bruised, scaly or hard, or into scars 0 Step 4: NovoFine® or damaged skin. 1 ® ® • Pull off the inner NovoFine Plus NovoTwist • Clean your injection Cartridge holder Dose counter Dose selector/ needle cap and site with an alcohol Count slowly: dose button throw it away (See swab. Let your skin Figure F). Do not try ® dry. Do not touch this PenFill cartridge 3 mL (example) to put the inner needle area again before 1-2-3-4-5-6 cap back on the injecting. needle. • Insert the needle

0 1 Threaded end Colored Rubber into your skin. Press (for needle attachment) band plunger and hold down the (Figure F) dose button until the (Figure A) A drop of insulin may appear at the needle tip. This is normal, but dose counter shows you must still check the insulin flow. “0”. Continue to keep the dose button pressed and keep the needle in your skin and slowly count to 6 (Figure J) (see Figure J). Insulin Aspart PenFill® 12

• Remove the needle from your skin. PenFill® cartridges in use: You may see a drop of insulin aspart at the needle tip after • Store the PenFill® cartridge you are currently using in the insulin injecting. This is normal and has no effect on the dose you just delivery device at room temperature below 86°F (30°C) for up to received. If blood appears after you take the needle out of your 28 days. Do not refrigerate. skin, press the injection site lightly with a cotton gauze and cover • The Insulin Aspart PenFill® cartridge you are using should be with an adhesive bandage, if necessary. Do not rub the area. thrown away after 28 days, even if it still has insulin left in it. After your injection General Information about the safe and effective use of Step 8: insulin aspart. • Lay your outer needle • Keep Insulin Aspart PenFill® cartridges and needles cap on a flat surface. out of the reach of children. Carefully, lead the needle • Do not share Insulin Aspart PenFill® cartridges or needles with tip into the outer needle other people. You may give other people a serious infection, or cap without touching the get a serious infection from them. needle (See Figure K) and • Always carry extra insulin of the same type(s) you use push the outer needle cap in case of loss or damage. completely on.

(Figure K) • Hold the black cartridge holder on the insulin delivery device and unscrew the needle counterclockwise (See Figure L). • Throw away (dispose Cartridge of) the needle in an holder FDA-cleared sharps container as your healthcare professional has instructed you. (Figure L) • Put your empty Insulin Aspart PenFill® cartridge and used needles in a FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles and PenFill® cartridges in your household trash. • If you do not have a FDA-cleared sharps disposal container, you may use a household container that is: made of a heavy-duty plastic, can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out, upright and stable during use, and leak-resistant and properly labeled to warn of hazardous waste inside the container. • When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. Do not reuse or share your needles or syringes with other people. For more information about the safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA’s website at: http://www.fda.gov/safesharpsdisposal. • Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container. Step 9: • Keep the 3 mL PenFill® cartridge in the device. Do not store your device with a needle attached. This will prevent infection or leakage of insulin and will make sure that you receive the right dose of insulin aspart.

• Put the pen cap on your device after each use 1 to protect the insulin from 0 light (See Figure M). (Figure M)

How should I store my Insulin Aspart PenFill® cartridge? • Do not freeze insulin aspart. Do not use insulin aspart if it has been frozen. • Keep insulin aspart away from heat or light. • Store the Insulin Aspart PenFill® cartridge without the needle attached. Before use: This Instructions for Use has been approved by the U.S. Food and • Store unused Insulin Aspart PenFill® cartridges in the Drug Administration. refrigerator at 36°F to 46°F (2°C to 8°C). Manufactured by: • Unused PenFill® cartridges may be used until the expiration date Novo Nordisk A/S printed on the label, if kept in the refrigerator. DK-2880 Bagsvaerd, Denmark • If insulin aspart is stored mistakenly outside of refrigeration Revised: 11/2019 between 47°F (9°C) to 86°F (30°C) prior to first use, it should be used within 28 days or thrown away. © 2002-2020 Novo Nordisk US19IA00014 1/2020